Advancing age predisposes us to a num- ber of neurodegenerative diseases, yet the underlying mechanisms are poorly understood. With some 70 mil- lion individuals affected, glaucoma is the world’s leading cause of irreversible blindness. Glaucoma is characterized by
the selective loss of retinal ganglion cells that
convey visual messages from the photoreceptive retina to the brain. Age is a major risk
factor for glaucoma, with disease incidence
increasing near exponentially with increasing age. Treatments that specifically target
retinal ganglion cells or the effects of aging
on glaucoma susceptibility are currently
lacking. On page 756 of this issue, Williams
et al. (1) report substantial advances toward
filling these gaps by identifying nicotinamide
adenine dinucleotide (NAD+) decline as a key
age-dependent risk factor and showing that
restoration with long-term dietary supplementation or gene therapy robustly protects
against neuronal degeneration.

Intraocular pressure increase is the secondmajor risk factor for glaucoma, and reduc-ing eye pressure slows disease progression inmost patients (2). Williams et al. conducteda systematic study of advancing age and theeffect of intraocular pressure increase ina mouse model that is prone to developingglaucoma. RNA sequencing was performedto elucidate the underlying factors by whichaging renders retinal ganglion cells vulner-able to damage from increased intraocularpressure. The most altered of all transcriptswere those encoding mitochondrial proteins.This coincided with the loss of mitochondrialstructure in the cell body and dendrites ofretinal ganglion cells, and preceded loss ofthese neurons.

Mitochondrial impairment is a well-established cause of retinal ganglion cell
loss in mitochondrial optic neuropathy
(3), and systemic mitochondrial dysfunction has been implicated in glaucoma (4)
and other age-related neurodegenerative
diseases (5). The finding that intraocular
pressure increase imparts further mitochondrial damage in the retina suggests
that both inherited and acquired mitochondrial dysfunction may predispose to retinal
ganglion cell loss in glaucoma.

By identifying NAD+ decline as a key
age-dependent risk factor for glaucoma,
Williams et al. reveal unprecedented protection by a single molecule against a complex
neurodegenerative disease. How can such a
simple manipulation have such profound effects? The NAD+/NADH pair is arguably the
central metabolic switch of eukaryotes. In
cells with healthy mitochondria, a high local
NADH concentration in this organelle will
signal an energetically replete state in which
the amount of adenosine 59-triphosphate
(ATP) in the cell is high and ATP-generating
oxidative phosphorylation in the mitochondria is paused by the relative lack of the
coupling substrate adenosine diphosphate
(ADP). This adaptive NAD+/NADH switch in
turn activates anabolic programs. However,
when oxidative phosphorylation is impaired,
increased NADH concentration is transmitted to the cytosol by efficient shuttles. This
represents a chronic reductive stress in

NEURODEGENERATIVE DISEASERelief for retinal neurons under pressureA dietary supplement may offer protection from loss of vision in glaucoma